Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000277.3(PAH):c.828G>T (p.Met276Ile)

CA229799

102859 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 192672cf-7c30-4845-8d37-a2ade95745fc

Approved on: 2021-01-17

Published on: 2021-04-09

HGVS expressions

NM_000277.3:c.828G>T

NM_000277.3(PAH):c.828G>T (p.Met276Ile)

NC_000012.12:g.102852829C>A

CM000674.2:g.102852829C>A

NC_000012.11:g.103246607C>A

CM000674.1:g.103246607C>A

NC_000012.10:g.101770737C>A

NG_008690.1:g.69774G>T

NG_008690.2:g.110582G>T

ENST00000307000.7:c.813G>T

ENST00000553106.5:c.828G>T

NM_000277.1:c.828G>T

NM_000277.2:c.828G>T

NM_001354304.1:c.828G>T

NM_001354304.2:c.828G>T

Uncertain Significance

PM2

PS1 PP4 PP3 PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.828G>T (p.Met276Ile) variant in PAH has been reported detected in a control clone from a subject who did not have PKU (PMID: 8364546, 9634518) This variant is absent from gnomAD, 1000G, ESP, and PAGE. Computational evidence is conflicting (Disease causing in MutationTaster, tolerated in SIFT, benign in PolyPhen2). There are 3 other missense changes at this amino acid: M276R (interpretation not provided in ClinVar, ID 102858); M276K (Likely Pathogenic in ClinVar, ID 102857); M276V (Likely Pathogenic in ClinVar, ID 102856). A different codon change leading to the same amino acid change, c.828G>A, has been interpreted as a variant of uncertain significance in ClinVar (ID 551519). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2.

PM2

Absent from gnomAD, 1000G, ESP, PAGE

PS1

c.828G>A (US)

PP4

Met276Ile was detected in a control clone from a subject who did not have PKU.

At base 1050 (amino acid 276) the reference clone was found to differ from the published sequence. The published sequence is ATG (methionine) while our reference clone contained ATT (isoleucine). The control clone from a subject who did not have PKU but who could have been a carrier. PubMed:2063869

PP3

Disease causing in MutationTaster, tolerated in SIFT, benign in PolyPhen2

PM5

M276R (not provided); M276K (LP); M276V (LP)

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